tbuckley/cabot-search huggingface dataset:
Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis
Authors: Amelia Shoemark, Helen Griffin, Gabrielle Wheway, Claire Hogg, Jane S. Lucas, Carme Camps, Jenny Taylor, Mary Carroll, Michael R. Loebinger, James D. Chalmers, Deborah Morris-Rosendahl, Hannah M. Mitchison, Anthony De Soyza, D. Brown, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, T. Fowler, A. Giess, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F Maleady-Crowe, M. McEntagart, F. Minneci, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O'Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood
Journal: European Respiratory Journal (2022)

Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis.This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
A genomic‐augmented multivariate prognostic model for the survival of natural‐killer/T‐cell lymphoma patients from an international cohort
Authors: Jing Quan Lim, Dachuan Huang, Jason Yongsheng Chan, Yurike Laurensia, Esther Kam Yin Wong, Daryl Ming Zhe Cheah, Burton Kuan Hui Chia, Wen‐Yu Chuang, Ming‐Chung Kuo, Yi‐Jiun Su, Qing‐qing Cai, Yanfen Feng, Huilan Rao, Li‐Na Feng, Pan‐Pan Wei, Jie‐Rong Chen, Bo‐Wei Han, Guo‐Wang Lin, Jun Cai, Yu Fang, Jing Tan, Huangming Hong, Yanhui Liu, Fen Zhang, Wenyu Li, Michelle L. M. Poon, Siok‐Bian Ng, Anand Jeyasekharan, Jeslin Chian Hung Ha, Lay Poh Khoo, Suk Teng Chin, Wan Lu Pang, Rebecca Kee, Chee Leong Cheng, Nicholas Francis Grigoropoulos, Tiffany Tang, Miriam Tao, Mohamad Farid, Kia Joo Puan, Jie Xiong, Wei‐Li Zhao, Chiea Chuen Khor, William Hwang, Won Seog Kim, Elias Campo, Patrick Tan, Bin Tean Teh, Wee‐Joo Chng, Olaf Rötzschke, Thomas Tousseyn, Hui‐Qiang Huang, Steve Rozen, Soon Thye Lim, Lee‐Yung Shih, Jin‐Xin Bei, Choon Kiat Ong
Journal: American Journal of Hematology (2022)

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.
Estimating typhoid incidence from community-based serosurveys: a multicohort study
Authors: Kristen Aiemjoy, Jessica C Seidman, Senjuti Saha, Sira Jam Munira, Mohammad Saiful Islam Sajib, Syed Muktadir Al Sium, Anik Sarkar, Nusrat Alam, Farha Nusrat Zahan, Md Shakiul Kabir, Dipesh Tamrakar, Krista Vaidya, Rajeev Shrestha, Jivan Shakya, Nishan Katuwal, Sony Shrestha, Mohammad Tahir Yousafzai, Junaid Iqbal, Irum Fatima Dehraj, Yasmin Ladak, Noshi Maria, Mehreen Adnan, Sadaf Pervaiz, Alice S Carter, Ashley T Longley, Clare Fraser, Edward T Ryan, Ariana Nodoushani, Alessio Fasano, Maureen M Leonard, Victoria Kenyon, Isaac I Bogoch, Hyon Jin Jeon, Andrea Haselbeck, Se Eun Park, Raphaël M Zellweger, Florian Marks, Ellis Owusu-Dabo, Yaw Adu-Sarkodie, Michael Owusu, Peter Teunis, Stephen P Luby, Denise O Garrett, Farah Naz Qamar, Samir K Saha, Richelle C Charles, Jason R Andrews
Journal: The Lancet Microbe (2022)

BackgroundThe incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.MethodsWe collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.FindingsThe longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1–81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3–9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.InterpretationThe approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.FundingBill & Melinda Gates Foundation.TranslationsFor the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.
Validity of Estimated Cardiorespiratory Fitness in Patients With Primary Breast Cancer
Authors: Meghan Michalski, Kylie Rowed, Jessica A. Lavery, Chaya S. Moskowitz, Catherine Capaci, Guro Stene, Elisabeth Edvardsen, Neil D. Eves, Lee W. Jones, Jessica M. Scott
Journal: JACC CardioOncology (2022)
Cost-Effectiveness of Catheter Ablation Versus Antiarrhythmic Drug Therapy in Atrial Fibrillation: The CABANA Randomized Clinical Trial
Authors: Derek S. Chew, Yanhong Li, Patricia A. Cowper, Kevin J. Anstrom, Jonathan P. Piccini, Jeanne E. Poole, Melanie R. Daniels, Kristi H. Monahan, Linda Davidson-Ray, Tristram D. Bahnson, Hussein R. Al-Khalidi, Kerry L. Lee, Douglas L. Packer, Daniel B. Mark
Journal: Circulation (2022)

In the CABANA trial (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation), catheter ablation did not significantly reduce the primary end point of death, disabling stroke, serious bleeding, or cardiac arrest compared with drug therapy by intention-to-treat, but did improve the quality of life and freedom from atrial fibrillation recurrence. In the heart failure subgroup, ablation improved both survival and quality of life. Cost-effectiveness was a prespecified CABANA secondary end point.
Care Fragmentation Is Associated with Increased Chronic Obstructive Pulmonary Disease Exacerbations in a U.S. Urban Care Setting
Authors: Karen C. Young, Daniel A. Meza, Basil Khuder, Sharon R. Rosenberg, Gabrielle Y. Liu, Jacqueline M. Kruser, Paul A. Reyfman, Ravi Kalhan
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Care Fragmentation Is Associated with Increased Chronic Obstructive Pulmonary Disease Exacerbations in a U.S. Urban Care Setting." American Journal of Respiratory and Critical Care Medicine, 206(8), pp. 1044–1047
Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases
Authors: Jing Li, Jun Jiang, Xun Bao, Vineet Kumar, Stephen C. Alley, Scott Peterson, Anthony J. Lee
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach. Experimental Design: Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions with efflux transporters were determined. Whole-body PBPK models integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration (Css,ave,br) to in vitro IC50 for HER2 inhibition, was used as a predictor of intracranial efficacy. Results: PBPK models predicted that following 1 cycle of standard dosing, tucatinib and lapatinib achieved similar Css,ave,br (14.5 vs. 16.8 nmol/L), while neratinib Css,ave,br (0.68 nmol/L) was 20-fold lower. Tucatinib and neratinib were equally potent for HER2 inhibition (IC50, 6.9 vs. 5.6 nmol/L), while lapatinib was less potent (IC50, 109 nmol/L). The model-predicted population mean TER in the human normal brain was 2.1 for tucatinib, but &amp;lt; 0.20 for lapatinib and neratinib. Conclusions: The PBPK modeling suggests that tucatinib induces sufficient HER2 inhibition (TER &amp;gt; 2.0) in not only brain metastases with a disrupted blood–brain barrier (BBB), but also micrometastases where the BBB largely remains intact. These findings, in line with available clinical pharmacokinetics and efficacy data, support the therapeutic value of tucatinib for treatment of brain metastases and warrant further clinical investigation for the prevention of brain metastases in patients with HER2-positive breast cancer.
Options for Detecting Risk of Aminoglycoside-Induced Ototoxicity in Neonates
Authors: Maya Muñoz Mahmood, Raymond K. Leung
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals
Authors: Claudio Gil Araujo, Christina Grüne de Souza e Silva, Jari Antero Laukkanen, Maria Fiatarone Singh, Setor Kwadzo Kunutsor, Jonathan Myers, João Felipe Franca, Claudia Lucia Castro
Journal: British Journal of Sports Medicine (2022)

Balance quickly diminishes after the mid-50s increasing the risk for falls and other adverse health outcomes. Our aim was to assess whether the ability to complete a 10- s one-legged stance (10-second OLS) is associated with all-cause mortality and whether it adds relevant prognostic information beyond ordinary demographic, anthropometric and clinical data.Anthropometric, clinical and vital status and 10-s OLS data were assessed in 1702 individuals (68% men) aged 51-75 years between 2008 and 2020. Log-rank and Cox modelling were used to compare survival curves and risk of death according to ability (YES) or inability (NO) to complete the 10-s OLS test.Overall, 20.4% of the individuals were classified as NO. During a median follow-up of 7 years, 7.2% died, with 4.6% (YES) and 17.5% (NO) on the 10-s OLS. Survival curves were worse for NO 10-s OLS (log-rank test=85.6; p<0.001). In an adjusted model incorporating age, sex, body mass index and comorbidities, the HR of all-cause mortality was higher (1.84 (95% CI: 1.23 to 2.78) (p<0.001)) for NO individuals. Adding 10-s OLS to a model containing established risk factors was associated with significantly improved mortality risk prediction as measured by differences in -2 log likelihood and integrated discrimination improvement.Within the limitations of uncontrolled variables such as recent history of falls and physical activity, the ability to successfully complete the 10-s OLS is independently associated with all-cause mortality and adds relevant prognostic information beyond age, sex and several other anthropometric and clinical variables. There is potential benefit to including the 10-s OLS as part of routine physical examination in middle-aged and older adults.
Time Course for Benefit and Risk With Ticagrelor and Aspirin in Individuals With Acute Ischemic Stroke or Transient Ischemic Attack Who Carry <i>CYP2C19</i> Loss-of-Function Alleles
Authors: Yuesong Pan, Xia Meng, Aoming Jin, S. Claiborne Johnston, Hao Li, Philip M. Bath, Xuewei Xie, Jing Jing, Jinxi Lin, Yilong Wang, Xingquan Zhao, Zixiao Li, Yong Jiang, Liping Liu, Hongqin Yang, Jiwei Cheng, Zhimin Wang, Yongjun Wang
Journal: JAMA Neurology (2022)

Dual antiplatelet therapy (DAPT) with ticagrelor and aspirin has been found to be effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA) in individuals who carry CYP2C19 loss-of-function (LOF) alleles; however, uncertainties remain about the time course of benefit and risk with ticagrelor and aspirin in these patients.To obtain time-course estimates of efficacy and risk with ticagrelor and aspirin after minor stroke or TIA in individuals with CYP2C19 LOF alleles.The Ticagrelor or Clopidogrel With Aspirin in High-risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) randomized clinical trial enrolled patients 40 years and older from 202 hospitals in China with acute minor stroke or TIA who carried CYP2C19 LOF alleles between September 23, 2019, and March 22, 2021, and were followed up for 90 days. All 6412 patients enrolled in the CHANCE-2 trial were included in this secondary analysis. Data were analyzed in October 2021.Ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2-90) or clopidogrel (300 mg on day 1 followed by 75 mg daily on days 2-90). All patients received aspirin (75-300 mg on day 1 followed by 75 mg daily for 21 days).The efficacy outcome was major ischemic event, defined as the composite of ischemic stroke or nonhemorrhagic death. Safety outcomes included moderate to severe bleeding and any bleeding.A total of 6412 patients were included (3205 in the ticagrelor and aspirin group and 3207 in the clopidogrel and aspirin group). The median (IQR) age was 65 (57-71) years, and 4242 patients (66%) were men. The reduction of major ischemic events with ticagrelor and aspirin predominately occurred in the first week (absolute risk reduction, 1.34%; 95% CI, 0.29 to 2.39) and attenuated but remained in the next 3 weeks (absolute risk reduction in the second week, 0.11%; 95% CI, -0.24 to 0.45; absolute risk reduction in the third week, 0.14%; 95% CI, -0.11 to 0.38; absolute risk reduction in the fourth week, 0.04%; 95% CI, -0.18 to 0.25). The risk of moderate to severe bleeding was consistently low in the ticagrelor and aspirin group. The absolute increase in any bleeding seen in the first week (0.87%; 95% CI, 0.25 to 1.50) remained in the next 3 weeks (absolute increase in the second week, 1.21%; 95% CI, 0.75 to 1.68; absolute increase in the third week, 0.33%; 95% CI, -0.05 to 0.72; absolute increase in the fourth week, 0.23%; 95% CI, -0.03 to 0.49).Among patients with minor stroke or TIA who carried CYP2C19 LOF alleles, benefit with ticagrelor and aspirin was present predominately in the first week, with additional small benefit accruing in the next 2 weeks.
Thromboxane–Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis
Authors: Toshio Suzuki, Jonathan A. Kropski, Jingyuan Chen, Erica J. Carrier, Xinping Chen, Taylor P. Sherrill, Nichelle I. Winters, Jane E. Camarata, Vasiliy V. Polosukhin, Wei Han, Anandharajan Rathinasabapathy, Sergey Gutor, Peter Gulleman, Carleen Sabusap, Nicholas E. Banovich, Harikrishna Tanjore, Michael L. Freeman, Yuji Tada, Lisa R. Young, Jason J. Gokey, Timothy S. Blackwell, James D. West
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated.
UK National Screening Committee's approach to reviewing evidence on artificial intelligence in breast cancer screening
Authors: Sian Taylor-Phillips, Farah Seedat, Goda Kijauskaite, John Marshall, Steve Halligan, Chris Hyde, Rosalind Given-Wilson, Louise Wilkinson, Alastair K Denniston, Ben Glocker, Peter Garrett, Anne Mackie, Robert J Steele
Journal: The Lancet Digital Health (2022)

Artificial intelligence (AI) could have the potential to accurately classify mammograms according to the presence or absence of radiological signs of breast cancer, replacing or supplementing human readers (radiologists). The UK National Screening Committee's assessments of the use of AI systems to examine screening mammograms continues to focus on maximising benefits and minimising harms to women screened, when deciding whether to recommend the implementation of AI into the Breast Screening Programme in the UK. Maintaining or improving programme specificity is important to minimise anxiety from false positive results. When considering cancer detection, AI test sensitivity alone is not sufficiently informative, and additional information on the spectrum of disease detected and interval cancers is crucial to better understand the benefits and harms of screening. Although large retrospective studies might provide useful evidence by directly comparing test accuracy and spectrum of disease detected between different AI systems and by population subgroup, most retrospective studies are biased due to differential verification (ie, the use of different reference standards to verify the target condition among study participants). Enriched, multiple-reader, multiple-case, test set laboratory studies are also biased due to the laboratory effect (ie, radiologists' performance in retrospective, laboratory, observer studies is substantially different to their performance in a clinical environment). Therefore, assessment of the effect of incorporating any AI system into the breast screening pathway in prospective studies is required as it will provide key evidence for the effect of the interaction of medical staff with AI, and the impact on women's outcomes.
Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies
Authors: Lucile Figueres, Sarah Bruneau, Caroline Prot-Bertoye, Gaëlle Brideau, Mélanie Néel, Camille Griveau, Lydie Cheval, Yohan Bignon, Jordan Dimitrov, Thomas Dejoie, Simon Ville, Christine Kandel-Aznar, Anne Moreau, Pascal Houillier, Fadi Fakhouri
Journal: Journal of the American Society of Nephrology (2022)

Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption.In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls.Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA.Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.